Defining the key pharmacophore elements of PF-04620110: Discovery of a potent, orally-active, neutral DGAT-1 inhibitor

Bioorganic and Medicinal Chemistry

Volumn 21, Issue 17, 2013, Pages 5081-5097

  Dow, Robert L ^a   Andrews, Melissa P ^a   Li, Jian Cheng ^a   Michael Gibbs, E ^a   Guzman Perez, Angel ^a   Laperle, Jennifer L ^a   Li, Qifang ^a   Mather, Dawn ^a   Munchhof, Michael J ^a   Niosi, Mark ^a   Patel, Leena ^a   Perreault, Christian ^a   Tapley, Susan ^a   Zavadoski, William J ^a  

^a PFIZER INC   (United States)

Author keywords

Carboxylic acid bioisotere; DGAT 1; Diabetes; Obesity; Passive permeability; Polar surface area

Indexed keywords

2 [4 [4 (4 AMINO 5 OXO 7,8 DIHYDROPYRIMIDO[5,4 F][1,4]OXAZEPIN 6(5H) YL)PHENYL]CYCLOHEXYL] N [1 (HYDROXYMETHYL) 2 METHYLPROPYL]ACETAMIDE; 2 [4 [4 (4 AMINO 5 OXO 7,8 DIHYDROPYRIMIDO[5,4 F][1,4]OXAZEPIN 6(5H) YL)PHENYL]CYCLOHEXYL] N CYCLOPENTYLACETAMIDE; 2 [4 [4 (4 AMINO 5 OXO 7,8 DIHYDROPYRIMIDO[5,4 F][1,4]OXAZEPIN 6(5H) YL)PHENYL]CYCLOHEXYL] N ETHYLACETAMIDE; 2 [4 [4 (4 AMINO 5 OXO 7,8 DIHYDROPYRIMIDO[5,4 F][1,4]OXAZEPIN 6(5H) YL)PHENYL]CYCLOHEXYL]ACETAMIDE; 2 [4 [4 (4 AMINO 7 OXO 7,8 DIHYDROPYRIMIDO[5,4 F][1,4]OXAZEPIN 6(5H) YL)PHENYL]CYCLOHEXYL]ACETIC ACID; 2 [4 [4 (4 AMINO 7,8 DIHYDROPYRIMIDO[5,4 F][1,4]OXAZEPIN 6(5H) YL)PHENYL]CYCLOHEXYL]ETHANOL; 4 [4 [(4 AMINO 8 METHYL 5 OXO 2,3 DIHYDROPYRIDO[3,4 F][1,4]OXAZEPIN 4(5H) YL)PHENYL]CYCLOHEXYL]ACETIC ACID; 4 AMINO 6 (4 METHYLPHENYL) 7,8 DIHYDROPYRIMIDO[5,4 F][1,4]OXAZEPIN 5(6H) ONE; 4 AMINO 6 (4 TERT BUTYLPHENYL) 7,8 DIHYDROPYRIMIDO[5,4 F][1,4]OXAZEPIN 5(6H) ONE; 4 AMINO 6 [4 [4 (2 HYDROXY 2 METHYLPROPYL)CYCLOHEXYL]PHENYL] 7,8 DIHYDROPYRIMIDO[5,4 F][1,4]OXAZEPIN 5(6H) ONE; 4 AMINO 6 [4 [4 (2 OXO 2 PYRROLIDIN 1YLETHYL)CYCLOHEXYL]PHENYL]7,8 DIHYDROPYRIMIDO[5,4 F][1,4]OXAZEPIN 5(6H) ONE; 4 AMINO 6 [4 [4 [(3 METHYL 1,2,4 OXADIAZOL 5 YL)METHYL]CYCLOHEXYL]PHENYL] 7,8 DIHYDROPYRIMIDO[5,4 F][1,4]OXAZEPIN 5(6H) ONE; 4 AMINO 6 [4 [4 [(4,5 DIMETHYL 4H 1,2,4 TRIAZOL 3 YL)METHYL]CYCLOHEXYL]PHENYL] 7,8 DIHYDROPYRIMIDO[5,4 F][1,4]OXAZEPIN 5(6H) ONE; 4 AMINO 6 [4 [4 [(5 METHYL 1,3,4 OXADIAZOL 2 YL)METHYL]CYCLOHEXYL]PHENYL] 7,8 DIHYDROPYRIMIDO[5,4 F][1,4]OXAZEPIN 5(6H) ONE; 4 AMINO 6 [4 [4 [(5 METHYL 1,3,4 THIADIAZOL 2 YL)METHYL]CYCLOHEXYL]PHENYL] 7,8 DIHYDROPYRIMIDO[5,4 F][1,4]OXAZEPIN 5(6H) ONE; 4 AMINO 6 [4 [4 [(5 METHYL 4H 1,2,4 TRIAZOL 3 YL)METHYL]CYCLOHEXYL]PHENYL] 7,8 DIHYDROPYRIMIDO[5,4 F][1,4]OXAZEPIN 5(6H) ONE; 4 AMINO 6 [4 [4 [2 (3 METHYL 4H 1,2,4 OXADIAZOL 5 YL)METHYL]CYCLOHEXYL]PHENYL] 7,8 DIHYDROPYRIMIDO[5,4 F][1,4]OXAZEPIN 5(6H) ONE; 4 AMINO 6 METHYL 7,8 DIHYDROPYRIMIDO[5,4 F][1,4]OXAZEPIN 5(6H) ONE; 4 AMINO 7,8 DIHYDROPYRIMIDO[5,4 F][1,4]OXAZEPIN 5(6H) ONE; [4 [4 (4 AMINO 2 METHYL 5 OXO 7,8 DIHYDROPYRIMIDO[5,4 F][1,4]OXAZEPIN 6(5H) YL)PHENYL]CYCLOHEXYL]ACETIC ACID; [4 [4 (4 AMINO 8,8 DIMETHY 5 OXO 2,3 DIHYDROPYRIDO[3,4 F][1,4]OXAZEPIN 4(5H) YL)PHENYL]CYCLOHEXYL]ACETIC ACID; [4 [4 (4 HYDROXY 5 OXO 7,8 DIHYDROPYRIMIDO[5,4 F][1,4]OXAZEPIN 6(5H) YL)PHENYL]CYCLOHEXYL]ACETIC ACID; [4 [4 (4 METHOXY 5 OXO 7,8 DIHYDROPYRIMIDO[5,4 F][1,4]OXAZEPIN 6(5H) YL)PHENYL]CYCLOHEXYL]ACETIC ACID; [4 [4 (6 AMINO 5 OXO 2,3 DIHYDROPYRIDO[3,4 F][1,4]OXAZEPIN 4(5H) YL)PHENYL]CYCLOHEXYL]ACETIC ACID; [4 [4 (AMINO 5 OXO 7,8 DIHYDROPYRIMIDO[5,4 F][1,4]OXAZEPIN 6(5H) YL)PHENYL]CYCLOHEXYL]ACETONITRILE; [4 [4 [4 (DIMETHYLAMINO) 5 OXO 7,8 DIHYDROPYRIMIDO[5,4 F][1,4]OXAZEPIN 6(5H) YL]PHENYL]CYCLOHEXYL]ACETIC ACID; [4 [4 [4 (METHYLAMINO) 5 OXO 7,8 DIHYDROPYRIMIDO[5,4 F][1,4]OXAZEPIN 6(5H) YL]PHENYL]CYCLOHEXYL]ACETIC ACID; DIACYLGLYCEROL ACYLTRANSFERASE 1; PF 04620110; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; DOSE RESPONSE; DRUG BINDING; DRUG BIOAVAILABILITY; DRUG CLEARANCE; DRUG EFFICACY; DRUG HALF LIFE; DRUG INHIBITION; DRUG POTENCY; DRUG SAFETY; LIPOPHILICITY; MALE; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; PHARMACOPHORE; RAT; STRUCTURE ACTIVITY RELATION; TRIACYLGLYCEROL BLOOD LEVEL;

RODENTIA;

CARBOXYLIC ACID BIOISOTERE; DGAT-1; DIABETES; OBESITY; PASSIVE PERMEABILITY; POLAR SURFACE AREA;

ADMINISTRATION, ORAL; ANIMALS; DIACYLGLYCEROL O-ACYLTRANSFERASE; DRUG EVALUATION, PRECLINICAL; ENZYME INHIBITORS; HALF-LIFE; HUMANS; MICE; MICE, INBRED C57BL; MICE, OBESE; OBESITY; OXADIAZOLES; OXAZEPINES; PROTEIN BINDING; RATS; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 84881370184     PISSN: 09680896     EISSN: 14643391     Source Type: Journal    
DOI: 10.1016/j.bmc.2013.06.045     Document Type: Article

References (31)

1. J.D. McGarry Diabetes 51 2002 7
2. K.G. Alberti, P. Zimmet, and J. Shaw Lancet 366 2005 1059
3. D.T. Stein, R. Dobbins, L. Szczepaniak, C. Malloy, and J.D. McGarry Diabetes 46 1997 23A
4. L.S. Szsczepaniak, E.E. Babcock, F. Schick, R.L. Dobbins, A. Garg, D.K. Burns, and J.D. McGarry Am. J. Physiol. 276 1999 E977
5. I. Huang-Doran, A. Sleigh, J.J. Rochford, S. O'Rahilly, and D.B. Savage J. Endocrinol. 207 2010 245
6. R.H. Unger, Y.-T. Zhou, and L. Orci Proc. Natl. Acad. Sci. U.S.A. 96 1999 2327
7. I. Shimonura, R.E. Hammer, S. Ikemoto, M.S. Brown, and J.L. Goldstein Nature 401 1999 73
8. R.A. Coleman, and D.P. Lee Prog. Lipid Synth. 43 2004 134
9. Koltun, D. O.; Zablocki, J. Enzymatic targets in the triglyceride synthesis pathway. In Annual Reports in Medicinal Chemistry, volume 45; Macor, J. E., Ed.: Academic Press, New York, 2010; pp 109-122.
10. H.J. Kayden, J.R. Senior, and F.H. Mattson J. Clin. Invest. 46 1967 1695
11. E.P. Kennedy Annu. Rev. Biochem. 26 1957 119
12. S. Cases, S.J. Smith, Y.W. Zheng, H.M. Myer, S.R. Lear, E. Sande, S. Novak, C. Collins, C.B. Welch, A.J. Lusis, S.K. Erickson, and R.V. Farese Jr. Proc. Natl. Acad. Sci. U.S.A. 95 1998 13018
13. P. Oelkers, A. Behari, D. Cromley, J.T. Billheimer, and S.L. Sturley J. Biol. Chem. 273 1998 26765
14. S. Cases, S.J. Stone, P. Zhou, E. Yen, B. Tow, K.D. Lardizabal, T. Voelker, and R.V. Farese Jr. J. Biol. Chem. 276 2001 38870
15. S.J. Smith, S. Cases, D.R. Jensen, H.C. Chen, E. Sande, B. Tow, D.A. Sanan, J. Raber, R.H. Eckel, and R.V. Farese Nat. Genet. 25 2000 87
16. H.C. Chen, S.J. Smith, Z. Ladha, D.R. Jensen, L.D. Ferreira, L.K. Pulawa, J.G. McGuire, R.E. Pitas, R.H. Eckel, and R.V. Farese J. Clin. Invest. 109 2002 1049
17. H.C. Chen, D.R. Jensen, H.M. Myers, R.H. Eckel, and R.V. Farese J. Clin. Invest. 111 2003 1715
18. R.L. Dow Acyl-CoA: Diacylglycerol Acyltransferase-1 Inhibition as an Approach to the Treatment of Type 2 Diabetes R.M. Jones, New Therapeutic Strategies for Type 2 Diabetes 2012 RSC Publishing Cambridge, UK 215 248
19. A.J. King, A.S. Judd, and A.J. Souers Expert Opin. Ther. Patents 20 2010 19
20. A.M. Birch, L.K. Buckett, and A.V. Turnbull Curr. Opin. Drug Disc. Dev. 13 2010 489
21. R.L. Dow Li, J-C.; Pence, M. P.; Gibbs, E. M.; LaPerle, J. L.; Litchfield, J.; Piotrowski, D. W.; Munchhof, M. J.; Manion, T. B.; Zavadoski, W. J.; Walker, G. S.; McPherson, R. K.; Tapley, S.; Sugarman, E.; Guzman-Perez, A.; DaSilva-Jardine, P. ACS Med. Chem. Lett. 2 2011 407
22. Fox, B. M.; Furukawa, N. H.; Hao, X.; Lio, K.; Inaba, T.; Jackson, S. M.; Kayser, F.; Labelle, M.; Kexue, M.; Matsui, T.; McMinn, D. L.; Ogawa, N.; Rubenstein, S. M.; Sagawa, S.; Sugimoto, K.; Suzuki, M.; Tanaka, M.; Ye, G. Yoshida, A.; Zhang, J. A. Preparation of fused bicyclic nitrogen-containing heterocycles, useful in the treatment or prevention of metabolic and cell proliferative diseases. WO 2004/047756A2, Chem. Abstr. 141:38623.
23. R.L. Dow, P.A. Carpino, J.R. Hadcock, S.C. Black, P.A. Iredale, P. DaSilva-Jardine, S.R. Schneider, E.S. Paight, D.A. Griffith, D.O. Scott, R.E. O'Connor, and C.I. Nduaka J. Med. Chem. 52 2009 2652
24. Brabec, M. J. Aldehydes and acetals. In Patty's Industrial Hygiene and Toxicology, Clayton, G. D.; Clayton, F. E., Eds.; John Wiley & Sons, Inc: New York, 1993; vol. IIB, 2629.
25. A.L. Hopkins, C.R. Groom, and A. Alex Drug Discovery Today 9 2004 430
26. L. Di, C. Whitney-Pickett, J.P. Umland, H. Zhang, X. Zhang, D.F. Gebhard, Y. Lai, J.J. Federico III, R.F. Davidson, R. Smith, E.L. Reyner, C. Lee, B. Feng, C. Rotter, M.V. Varma, S. Kempshall, K. Fenner, A.F. El-Kattan, T.E. Liston, and M.D. Troutman J. Pharm. Sci. 100 2011 4974
27. N.A. Meanwell J. Med. Chem. 54 2011 2529
28. C.J. Villaneuva, M. Monetti, M. Shih, P. Zhou, S.M. Watkins, S. Bhanot, and R.V. Farese Jr. Hepatology 50 2009 434
29. M. Kusunoki, K. Tsutsumi, T. Hara, H. Ogawa, T. Nakamura, F. Sakakibara, Y. Fukuzawa, T. Suga, S. Kakumu, and Y. Nakaya Metabolism 51 2002 792
30. W.L. Jorgensen, D.S. Maxwell, and J. Tirado-Rives J. Am. Chem. Soc. 118 1996 11225
31. G.A. Kaminski, R.A. Friesner, J. Tirado-Rives, and W.J. Jorgensen J. Phys. Chem. B 105 2001 6474